The long-term objective of this research is to understand the molecular mechanisms of bacterial host cell invasion both in vitro and in vivo. Clinical evidence indicates improved prognosis for patients on a statin regimen prior to bacterial sepsis. While some of these beneficial effects have been attributed to improved hemodynamics or immunomodulation, we have recently found that therapeutic concentrations of simvastatin in vitro inhibits host invasion by Staphylococcus aureus, the most common etiologic agent in sepsis. Inhibition appears to be due primarily to the depletion of isoprenoid intermediates by simvastatin within the cholesterol biosynthesis pathway rather than to the depletion of cholesterol itself. Simvastatin also led to the cytosolic accumulation of CDC42 coupled to the phosphoinositide 3-kinase (PI3K) regulatory subunit p85. The proposed hypothesis is that simvastatin inhibits host invasion in part through sequestration of PI3K isoforms within the cytosol. Proposed studies will use genetic approaches to sequester PI3K within the cytosol and assess whether host invasion is decreased. In vivo models of infection will be used to assess whether the inhibition of host invasion increases antibiotic efficacy and prevents chronic, persistent infection, or conversely, whether simvastatin inhibition of uptake by non-professional phagocytes impairs innate clearance. Together, the proposed experiments will address a potentially novel mechanism in the action of statins that could lead to more directed therapeutics to circumvent issues in statin use as an adjunct therapy for infectious disease. The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. PUBLIC HEALTH RELEVANCE: The cholesterol-lowering drugs known as statins have a number of non-cholesterol lowering benefits, including a decreased risk of death due to systemic infection. This proposed work will engage undergraduate and master's level students in the investigation of the protective effect of statins, pursuing the question of whether statins block infection, with an overall goal of developing adjunctive therapies for the treatment of infectious disease. [unreadable] [unreadable] [unreadable]